Sexually Transmitted Infection
Conditions
Keywords
Doxycycline, Pharmacokinetics, PK Sampling
Brief summary
The purpose of this study is to evaluate the effect of body changes on doxycycline concentrations for different dosing schedules. This study will involve a single dose phase and a multiple dose phase. Healthy individuals who do not have a sexually transmitted infection (STI), including acute (e.g., gonorrhea or chlamydia) or chronic (e.g., HIV or HSV-2) infections will be enrolled in this study. Study participants will be randomized to a dosing schedule in each phase and come to the research clinic throughout their time on study for sample collection. Study participants that choose to enroll in this study will be enrolled for about 37 days.
Detailed description
Doxycycline is a Food and Drug Administration (FDA) approved broad-spectrum, second-generation tetracycline antibiotic that is generally well-tolerated and has been widely used as primary prophylaxis for bacterial and parasitic infections. While the pharmacokinetics (PK) of doxycycline in blood are well-described, knowledge gaps exist with intermittent dosing and establishing adherence thresholds for prophylactic use. Further, the multi-compartment distribution of the doxycycline has not been extensively characterized. The purpose of this study will be to characterize pharmacologic parameters for daily and non-daily doxycycline use and establish adherence cutoffs for daily and non-daily use.
Interventions
DRUGSingle-Dose PK Phase - DR Group
One 200 mg doxycycline hyclate delayed release (DR) tablet
DRUGSingle-Dose PK Phase - IR Group
Two 100 mg doxycycline hyclate immediate-release (IR) tablets
DRUGMulti-Dose PK Phase - Daily Group
One 200 mg doxycycline hyclate delayed release (DR) tablet every 24 hours
DRUGMulti-Dose PK Phase - Intermittent Group
One 200 mg doxycycline hyclate delayed release (DR) tablet every 72 hours
Sponsors
HIV Prevention Trials Network
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Sixteen (16) participants (approximately 8 males and 8 females) will undergo two randomization sequences upon enrollment into the study. In the single dose phase, participants will be randomized (1:1) to take a dose of 200mg doxycycline hyclate as either 1) 1x 200mg delayed release (DR) tablet or 2) 2x100mg immediate release (IR) tablets. Following administration of this single dose, participants will undergo semi-intensive PK sampling over a 14-day period. In the multiple dose phase, participants will also be randomized (1:1) to receive 200mg doxycycline hyclate (as a DR tablet) either daily (every 24 hours) or intermittently (every 72 hours) for 10 days. Both randomizations (IR vs DR and daily vs intermittent frequency) will be stratified by sex. All doses will be directly observed by study staff. Participants will be followed for 14 days after their last dose. PK sampling will occur at designated times over the course of the study.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Aged 18 to 65 years of age at the time of screening 2. Able and willing to follow study participation requirements and provide informed consent to take part in the study 3. Has a non-reactive/negative HIV test results at screening per applicable algorithm 4. Has and is able to maintain a caput (head) of hair, that has not been chemically treated (defined as hair that has been bleached, permed, relaxed or dyed/colored) and is greater than one centimeter in length for the duration of the study 5. For females of reproductive potential: Has a negative urine pregnancy test at screening 6. For females of reproductive potential: Using at least two effective methods of contraception for at least 30 days (inclusive) prior to enrollment and intending to use two effective methods of contraception for the duration of study participation. It is strongly recommended that at least one barrier method (e.g. condoms) in addition to a hormonal contraception method be used. Examples of acceptable and effective methods include: 1. Hormonal methods (oral pills, vaginal ring, depo, transdermal or implant) 2. Intrauterine device (IUD) inserted at least 30 days prior to enrollment 3. Surgical sterilization (of participant or partner(s)) including bilateral tubal ligation or vasectomized male partners 4. Barrier methods (condom with/without spermicide, sponge, cervical cap, diaphragm) 5. Self-identifies as having same sex partners 6. Self-reported sexually abstinent as defined by abstaining from penile-vaginal intercourse for 90 days prior to enrollment and intending to remain sexually abstinent for the duration of study participation 7. Has access to a smartphone and/or laptop and is able and willing to participate in video-based communications with study staff for directly observed dosing requirements 8. In good general health, in the opinion of the investigator of record (IoR) or designee and has no medical condition that would adversely impact the conduct of the study (inclusive of self-reported conditions and/or those found upon medical history and examination or in available medical records). This includes, but is not limited to, having an intact, healthy gastrointestinal tract (without damage or functional disruption) and the ability to swallow pills
Exclusion criteria
1. Per participant report, planned or active use of any anticonvulsants at screening and an unwillingness to restrict use of certain medications (iron, antacids, etc.) for the duration of the study 2. For females of reproductive potential: Pregnant or currently breastfeeding, or intends to become pregnant and/or breastfeed during the study 3. Has any of the following laboratory abnormalities: 1. An estimated calculated creatinine clearance (CrCl) less than 60 mL/min by the Cockcroft-Gault formula at screening 2. Positive for hepatitis B surface antigen (HBsAg) at screening 3. Has a Grade 2 or higher clinically significant laboratory abnormality as defined by The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 - July 2017 (exception: a CrCl ≥ 60 mL/min at enrollment is permissible for enrollment) 4. Per participant reported symptoms or clinical and/or laboratory diagnosis of an active pharyngeal, anorectal, or reproductive tract infection (RTI) requiring treatment at screening and enrollment per current US Centers for Disease Control and Prevention (CDC) guidelines (https://www.cdc.gov/std/treatment-guidelines/default.htm). Infections requiring treatment include Neisseria gonorrhoeae (GC), Chlamydia trachomatis (CT), syphilis, active herpes simplex virus (HSV) lesions, or symptomatic genital warts, chancroid, pelvic inflammatory disease (PID), bacterial vaginosis (BV), symptomatic vaginal candidiasis, and trichomoniasis 5. Participation in research studies involving drugs, products, or vaccines within 30 days of the enrollment and for the duration of the study 6. Has donated blood within 8 weeks of enrollment of approximately 1 pint (550 mL) 7. Has a known allergy (adverse reaction) to any of the components of the study product, including known hypersensitivity to tetracycline-class antibiotics 8. Prior use of doxycycline or any other tetracycline-class antibiotic within 30 days prior to enrollment 9. Has an active infection that may be responsive to treatment with doxycycline or another tetracycline antibiotic 10. Has evidence or history of any other condition (e.g., gastrectomy, seizure disorder), that, in the opinion of the IoR or designee, would make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving study objectives
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum observed plasma concentration (Cmax) for 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) plasma doxycycline hyclate Cmax (ng/mL units) |
| Minimum observed plasma concentration (Cmin) for 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) plasma doxycycline hyclate Cmin (ng/mL units) |
| Time to reach maximum plasma concentration (Tmax) of 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) plasma doxycycline hyclate Tmax (hours units) |
| Plasma half-life (T1/2) of 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) plasma doxycycline hyclate half-life (T1/2, hours units) |
| Area Under the Concentration-Time Curve in plasma From One to 336 Hours After Dosing (AUC0-24) of 200mg doxycycline hyclate. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) plasma doxycycline hyclate area under the concentration time curve (AUC)0-inf (ng\*hr/mL units) |
| Plasma concentrations at 24 hours (C24) post last dose of doxycycline following 10 days of daily or intermittent dosing. | 24 hours post last dose of the multiple dose phase. | Median (IQR) plasma concentration at 24 hours post last dose (ng/mL units) |
| Plasma concentrations at 48 hours (C48) post last dose of doxycycline following 10 days of daily or intermittent dosing. | 48 hours post last dose of the multiple dose phase. | Median (IQR) plasma concentration at 48 hours post last dose (ng/mL units) |
| Plasma concentrations at 72 hours (C72) post last dose of doxycycline following 10 days of daily or intermittent dosing. | 72 hours post last doseof the multiple dose phase. | Median (IQR) plasma concentration at 72 hours post last dose (ng/mL units) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of gastrointestinal (GI)-related adverse events reported after doxycycline hyclate dosing during the multiple dose phase. | Study visit days 14-23 | Number of GI-related adverse events during 10 days of daily or intermittent doxycycline dosing |
| Number of gastrointestinal (GI)-related adverse events reported after doxycycline hyclate dosing after the multiple dose phase. | Up to 14 days post last dose. | Number of GI-related adverse events for 14 days following final daily or intermittent dose (through the Final/Day 37 visit) |
| Maximum observed dried blood spot (DBS) concentration (Cmax) for 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) DBS doxycycline hyclate Cmax (ng/mL units) |
| Minimum observed dried blood spot (DBS) concentration (Cmin) for 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) DBS doxycycline hyclate Cmin (ng/mL units) |
| Time to reach maximum dried blood spot (DBS) concentration (Tmax) of 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) DBS doxycycline hyclate Tmax (hours units) |
| Dried blood spot (DBS) half-life (T1/2) of 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) DBS doxycycline hyclate half-life (T1/2, hours units) |
| Area Under the Concentration-Time Curve in dried blood spots (DBS) From One to 336 Hours After Dosing (AUC0-24) of 200mg doxycycline hyclate. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) DBS doxycycline hyclate area under the concentration time curve (AUC)0-inf (ng\*hr/mL units) |
| Maximum observed anorectal fluid concentration (Cmax) for 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) anorectal doxycycline hyclate Cmax (ng/swab units) |
| Minimum observed anorectal fluid concentration (Cmin) for 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) anorectal doxycycline hyclate Cmin (ng/swab units) |
| Time to reach maximum anorectal fluid concentration (Tmax) of 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) anorectal doxycycline hyclate Tmax (hours units) |
| Anorectal fluid half-life (T1/2) of 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) anorectal doxycycline hyclate half-life (T1/2, hours units) |
| Area Under the Concentration-Time Curve in anorectal fluid From One to 336 Hours After Dosing (AUC0-24) of 200mg doxycycline hyclate. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) anorectal doxycycline hyclate area under the concentration time curve (AUC)0-inf (ng\*hr/swab units) |
| Maximum observed vaginal fluid concentration (Cmax) for 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) vaginal doxycycline hyclate Cmax (ng/swab units) |
| Minimum observed vaginal fluid concentration (Cmin) for 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) vaginal doxycycline hyclate Cmin (ng/swab units) |
| Time to reach maximum vaginal fluid concentration (Tmax) of 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) vaginal doxycycline hyclate Tmax (hours units) |
| Vaginal fluid half-life (T1/2) of 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) vaginal doxycycline hyclate half-life (T1/2, hours units) |
| Area Under the Concentration-Time Curve in vaginal fluid From One to 336 Hours After Dosing (AUC0-24) of 200mg doxycycline hyclate. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Median (IQR) vaginal doxycycline hyclate area under the concentration time curve (AUC)0-inf (ng\*hr/swab units) |
| Maximum observed pooled urine concentration (Cmax) for 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Mean (95% CI) urine doxycycline hyclate Cmax (ng/mL units) |
| Minimum observed pooled urine concentration (Cmin) for 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Mean (95% CI) urine doxycycline hyclate Cmin (ng/mL units) |
| Time to reach maximum pooled urine concentration (Tmax) of 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Mean (95% CI) urine doxycycline hyclate Tmax (hours units) |
| Pooled urine half-life (T1/2) of 200mg doxycycline hyclate after a single dose. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Mean (95% CI) urine doxycycline hyclate half-life (T1/2, hours units) |
| Area Under the Concentration-Time Curve in urine From One to 336 Hours After Dosing (AUC0-24) of 200mg doxycycline hyclate. | 1, 2, 3, 4, 6, 8, 24, 72, 96, 168, 240, and 336 hours post dose. | Mean (95% CI) urine doxycycline hyclate area under the concentration time curve (AUC)0-inf (ng\*hr/mL units) |
| Dried blood spot (DBS) concentrations at 24 hours (C24) post last dose of doxycycline following 10 days of daily or intermittent dosing. | 24 hours post last dose of the multiple dose phase. | Median (IQR) DBS concentration at 24 hours post last dose (ng/mL units) |
| Dried blood spot (DBS) concentrations at 48 hours (C48) post last dose of doxycycline following 10 days of daily or intermittent dosing. | 48 hours post last dose of the multiple dose phase. | Median (IQR) DBS concentration at 48 hours post last dose (ng/mL units) |
| Dried blood spot (DBS) concentrations at 72 hours (C72) post last dose of doxycycline following 10 days of daily or intermittent dosing. | 72 hours post last dose of the multiple dose phase. | Median (IQR) DBS concentration at 72 hours post last dose (ng/mL units) |
| Urine concentrations at 24 hours (C24) post last dose of doxycycline following 10 days of daily or intermittent dosing. | 24 hours post last dose of the multiple dose phase. | Median (IQR) urine concentration at 24 hours post last dose (ng/mL units) |
| Urine concentrations at 48 hours (C48) post last dose of doxycycline following 10 days of daily or intermittent dosing. | 48 hours post last dose of the multiple dose phase. | Median (IQR) urine concentration at 48 hours post last dose (ng/mL units) |
| Urine concentrations at 72 hours (C72) post last dose of doxycycline following 10 days of daily or intermittent dosing. | 72 hours post last dose of the multiple dose phase. | Median (IQR) urine concentration at 72 hours post last dose (ng/mL units) |
| Anorectal fluid concentrations at 24 hours (C24) post last dose of doxycycline following 10 days of daily or intermittent dosing. | 24 hours post last dose of the multiple dose phase. | Median (IQR) anorectal concentration at 24 hours post last dose (ng/swab units) |
| Anorectal fluid concentrations at 48 hours (C48) post last dose of doxycycline following 10 days of daily or intermittent dosing. | 48 hours post last dose of the multiple dose phase. | Median (IQR) anorectal concentration at 48 hours post last dose (ng/swab units) |
| Anorectal fluid concentrations at 72 hours (C72) post last dose of doxycycline following 10 days of daily or intermittent dosing. | 72 hours post last dose of the multiple dose phase. | Median (IQR) anorectal concentration at 72 hours post last dose (ng/swab units) |
| Vaginal fluid concentrations at 24 hours (C24) post last dose of doxycycline following 10 days of daily or intermittent dosing. | 24 hours post last dose of the multiple dose phase. | Median (IQR) vaginal concentration at 24 hours post last dose (ng/swab units) |
| Vaginal fluid concentrations at 48 hours (C48) post last dose of doxycycline following 10 days of daily or intermittent dosing. | 48 hours post last dose of the multiple dose phase. | Median (IQR) vaginal concentration at 48 hours post last dose (ng/swab units) |
| Vaginal fluid concentrations at 72 hours (C72) post last dose of doxycycline following 10 days of daily or intermittent dosing. | 72 hours post last dose of the multiple dose phase. | Median (IQR) vaginal concentration at 72 hours post last dose (ng/swab units) |
Countries
United States
Contacts
STUDY_CHAIRMackenzie Cottrell, PharmD, MS
University of North Carolina, Chapel Hill
STUDY_CHAIRMark Marzinke, PhD
Johns Hopkins University
Outcome results
None listed